The invention relates to the use of the functionally selective muscarinic M1 agonist talsaclidine for the preparation of a medicament for inhibiting xcex2-amyloid synthesis and reduction in synthesis of tau proteins.
Amyloid xcex2-peptides (Axcex2) are strongly aggregating peptides with approximate molecular masses of 4 kDa. The predominant forms, Axcex240 and Axcex242, are 40 and 42 amino acid residues in length, and are the major proteinaceous constituents of brain amyloid deposits in a variety of diseases. Axcex242 is an early and central component of amyloid in diffuse and senile plaques, while Axcex240 is the major peptide form in amyloid deposits in the cerebral microvasculature. Axcex240 and Axcex242 are derived by endoproteaolysis of the larger amyloid precursor protein (APP) by the combined activities of xcex2-secretases that cleaves at the amino-terminus, and a xcex3-secretase that cleaves at the C-terminus, respectively, of the Axcex2 domain. Alternative amino-terminal cleavage by xcex1-secretase within the Axcex2 domain results in the generation of non-amyloidogenic fragments. Because Axcex2 peptides readily aggregate into insoluble amyloid plaques, lowering their generation is a major objective for the design of therapeutic and preventive strategies for the treatment of a variety of diseases. Tau proteins are central to the neuropathology of, for instance, Alzheimer""s disease and tau levels are increased in affected individuals.
Surprisingly, it has been found that the selective muscarinic M1 agonist talsaclidine selectively decreases the cerebrospinal fluid (CSF) level of Axcex242, Axcex240, and tau protein; Axcex240 and tau protein dose dependently. Accordingly, one embodiment of the current invention relates to the use of talsaclidine for the preparation of a medicament for lowering the level of Axcex240, Axcex242, and tau protein.
In a preferred embodiment the invention relates to the use of talsaclidine for the preparation of a medicament for the treatment or prophylaxis of diseases associated with the formation of diffuse and senile plaques.
Furthermore, the invention relates to the use of talsaclidine for the preparation of a medicament for the treatment or prophylaxis of diseases associated with the formation of Axcex240-, Axcex242-, and tau-containing plaques, preferably of Axcex242-containing plaques.
Moreover, the invention relates to the use of talsaclidine for the preparation of a medicament for the treatment or prophylaxis of amyloidosis associated with the formation of Axcex240, Axcex242 and tau. Preferably the invention relates to the use of talsaclidine for the preparation of a medicament for the treatment or prophylaxis of amyloidosis associated with the formation of Axcex242.
In particular, the invention relates to the use of talsaclidine for the preparation of a medicament for the treatment or prophylaxis of brain amyloidosis.
Furthermore, the invention relates to the use of talsaclidine for the preparation of a medicament for the treatment or prophylaxis of vascular amyloidosis and age-related amyloidosis.
Moreover, the invention relates to the use of talsaclidine for the preparation of a medicament for the treatment of patients suffering from mild to moderate dementia of Alzheimer-type (DAT). Patients suffering from mild to moderate dementia of Alzheimer-type show values of about 12-28, preferably 14-28 in the Mini Mental State Examination (MMSE).
Furthermore the invention relates to the use of talsaclidine for the preparation of a medicament for the prophylactic treatment of mild to moderate dementia of Alzheimer-type.
Moreover, the invention relates to the use of talsaclidine for the preparation of a medicament for the treatment of patients suffering from mild cognitive impairment (MCI) and mild age associated memory impairment (AAMI). Patients suffering from mild MCI and AAMI show values of about 23-28 in the Mini Mental State Examination (MMSE).
Furthermore the invention relates to the use of talsaclidine for the preparation of a medicament for the prophylactic treatment of mild cognitive impairment (MCI) and mild age associated memory impairment (AAMI).